Treatment of obese patients with the peptide oxyntomodulin (Oxm) has been shown effective in obtaining weight loss, and several attempts have been made to obtain a useful medicament based on the native human oxyntomodulin sequence or modifications thereof [see, for example, WO03/022304 and WO2004/062685]. Oxyntomodulin is known to activate both the GLP-1 (glucagon-like peptide 1) receptor and the glucagon receptor, and it has been suggested that the GLP-1 receptor is essential for the anorectic function of Oxm.
Oxyntomodulin is derived from proglucagon, which is a 158 amino acid peptide processed differently in different organs. Whereas glucagon (29 amino acids in length; His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr) is produced in the pancreas, the longer 37 amino acid peptide oxyntomodulin (His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Lys-Arg-Asn-Arg-Asn-Asn-Ile-Ala) is produced in the intestine and brain. Oxyntomodulin consists of the full length glucagon and a C-terminal octapeptide (termed “intervening peptide 1” or IP-1, sequence Lys-Arg-Asn-Arg-Asn-Asn-Ile-Ala). Both glucagon and IP-1 fail to affect food intake when administered separately (Dakin, C. L. et al. (2001), Endocrin. 142, 4244-4250).
Both peptides are a substrate for the endogenous enzyme dipeptidyl peptidase which cleaves at the C-terminal side of Ser2 (Zhu, L. et al. (2003), J. Biol. Chem. 278, 22418-22423). Moreover it is found that a proteolytic fragment of glucagon is liberated following cleavage of glucagon at the Arg17-Arg18 amino acid doublet (Blache, P. at al. (1993) J. Biol. Chem. 268, 21748-21753).